Sickle cell disease (SCD) is characterized by microvascular disease from inflammation and oxidative damage. Many adult patients with SCD suffer from cognitive impairment (CI), a serious complication responsible for severe functional limitations, and whose pathogenesis, risk factors, and natural history are unknown. Thus, elucidating CI holds high public health significance because it will allow the development of preventive and therapeutic strategies. In this first RO1 application, Dr. Novelli builds on his prir work on the vascular biology of SCD and proposes that CI is caused by specific, quantifiable, cerebral microvascular disease, in turn caused by inflammation and oxidative damage from pathologic reactive oxygen species (ROS). He specifically proposes that the inflammatory protein TSP1 promotes ROS generation that leads to cerebrovascular disease and ultimately CI. This novel pathway has never been tested in SCD because of the lack of comprehensive longitudinal assessments of risk factors of CI and adequate MRI methods to image the cerebral microvasculature. This proposal addresses these barriers via the application of 7T MRI neuroimaging in a well- characterized cohort of adults with SCD in combination with neurocognitive testing and blood biomarkers of inflammation and oxidative damage. This project is expected to generate critical new knowledge on the pathophysiology of CI and its risk factors as targets for early prevention, screening and intervention. This study leverages Dr. Novelli's expertise and current work in the vascular biology of SCD, and builds on Dr. Novelli's ongoing study in this cohort, supported by institutional funds, a strong clinical research infrastructure ad existing collaborative efforts with investigators expert in Neuroepidemiology, Biostatistics, Neuroimaging, Psychiatry, Neuropsychology, and microvascular disease. These collaborations have already led to strong, published, preliminary results that support this application. This project is also highly innovative because it tests a new paradigm of microvascular dysfunction-related CI in SCD with state-of-the-art technology. Our scientific questions are articulated into two aims, Aim1, cross-sectional and Aim 2, longitudinal. In Aim 1 we first plan to extend and confirm in a larger cohort (n=160 patients and 70 controls) our preliminary results showing worse cognitive function and burden of 7T MRI microvascular abnormalities in patients as compared to controls (H1). Within patients, we will then test the hypothesis that worse 7T MRI abnormalities are linked to worse cognitive function (H2) and that high TSP1 levels are associated with both worse 7T MRI abnormalities and cognitive function (H3). Finally, we test the hypothesis that ROS mediates the association between TSP1 and these outcomes (H4). In Aim 2, these hypotheses will be tested in a longitudinal design with repeated MRI at 3 years and repeated blood and cognitive measures at 3 and 5 years.